NANOPARTICLE-ENABLED TRANSDERMAL DELIVERY OF CANNABIDIOL AND RELATED CANNABINOIDS: CARRIER CHEMISTRY, QUALITY-BY-DESIGN FORMULATION, AND THERAPEUTIC TRANSLATION

Abstract

Cannabidiol (CBD) and related phytocannabinoids have attracted sustained pharmaceutical interest for their anti-inflammatory, analgesic and antioxidant properties, yet their clinical utility is persistently constrained by negligible aqueous solubility, extensive hepatic first-pass metabolism, and markedly variable oral bioavailability. Transdermal delivery offers a mechanistic route around these limitations by avoiding the gastrointestinal tract and hepatic first pass altogether. Realising this route in practice, however, requires overcoming the stratum corneum barrier, and a broad family of nanocarriers vesicular lipid systems (liposomes, ethosomes, transfersomes), solid lipid nanoparticles and nanostructured lipid carriers, and mesoporous inorganic carriers such as mesoporous silica nanoparticles (MSN) and magnesium aluminometasilicate (MAS) has been developed to that end. This review synthesises the published literature on nanoparticle-based transdermal delivery of cannabinoids and structurally comparable lipophilic actives, covering carrier chemistry and comparative performance, physical and chemical permeation-enhancement strategies, Quality-by-Design (QbD) approaches to nanoparticle and patch optimisation, general principles of transdermal patch evaluation, in-vitro release and permeation kinetics, stability considerations, preclinical and clinical anti-inflammatory evidence, carrier biosafety, the evolving regulatory landscape for cannabinoid-containing topical products, and the emerging role of artificial intelligence in formulation design. Across this evidence base, mesoporous nanoparticle carriers combined with a Quality-by-Design-optimised transdermal patch represent a mechanistically well-supported and increasingly well-evidenced platform for cannabinoid delivery, though unresolved questions in chronic dermal nanotoxicology and an unsettled regulatory environment remain the principal barriers to clinical translation.